Despite decades of investigation and innumerable studies, an understanding of the role of the autonomic nervous system in regulating skeletal muscle blood flow during exercise remains elusive. It is well known that muscarinic receptors can mediate smooth muscle relaxation in the arterial vasculature of skeletal muscle, but their participation in the skeletal muscle hyperemia at the onset of exercise is uncertain. Relaxation of vascular smooth muscle can also occur via activation of ATP sensitive potassium channels. Preliminary data described in this application implicate these channels as the transduction mechanism for exercise-induced skeletal muscle vasodilation. The evidence that the sympathetic nervous system constrains blood flow to dynamically exercising muscle is contradictory, but a recent study from the applicant's laboratory established that there is alpha 1 adrenergic restraint of blood flow to active skeletal muscle. Pilot data included in this application also demonstrate the existence of tonic alpha 2 receptor mediated vasoconstriction in active skeletal muscles during dynamic exercise. The working hypothesis underlying this proposal is that the autonomic nervous system does not affect the rate or magnitude of vasodilation in skeletal muscle at the onset of exercise, but actively constrains blood flow to active skeletal muscle during steady state exercise. To elucidate the role of the autonomic nervous system in the control of skeletal muscle blood flow during exercise, the following specific aims are proposed: Aim 1: To determine if there is an autonomic component to the rapid vasodilation which occurs in skeletal muscle at the onset of dynamic exercise. Aim 2: To examine the mechanism of sympathetic vasoconstriction in dynamically exercising skeletal muscle. The ability to deliver agonists and antagonists to a discrete vascular bed in conscious, exercising animals is a major strength of the protocols described. The proposed studies will provide valuable new information regarding the basic physiological mechanisms by which blood flow is regulated to skeletal muscle at rest and during exercise. This issue is of fundamental importance to be addressed by straightforward experiments. In addition, an understanding of how ischemia affects alpha 1 and alpha 2 mediated vasoconstriction may have important implications for individuals with peripheral vascular disease.